Date of Graduation

8-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Cell & Molecular Biology (PhD)

Degree Level

Graduate

Department

Cell & Molecular Biology

Advisor/Mentor

Moradi, Mahmoud

Committee Member

Sakon, Josh

Second Committee Member

Wang, Yong

Third Committee Member

Fan, Chenguang

Keywords

Molecular dynamics; Chemo-mechanical coupling; Influenza

Abstract

Proteins are dynamic entities that undergo conformational changes essential for their biological functions. These structural changes often correspond with chemical events such as lipid interactions or environmental changes like protonation or acidification. Understanding the complex relationship between these chemical perturbations and the resultant mechanical responses is crucial for elucidating protein mechanisms. This dissertation investigates the chemo-mechanical coupling in the conformational dynamics of the bacterial ABC transporter Sav1866 and the impact of protonation on the Influenza virus hemagglutinin HA0. Using molecular dynamics simulations, we explore the conformational landscapes of Sav1866 and HA0. Our study examines how varying lipid compositions affect the dynamics of Sav1866, revealing distinct conformational behaviors. Notably, Sav1866 demonstrates unique channel-like behavior in DMPC lipid environments, with both cytoplasmic and periplasmic gates open throughout the simulation, unlike the transition observed in POPE lipids. Specific lipid-protein interactions, including crucial hydrogen bonds, are shown to influence these conformational states, underscoring the lipid-dependent specificity in the function of ABC transporters. Furthermore, our research delves into the effects of protonation on HA0’s conformational dynamics, particularly focusing on the residue H106 in the HA2 region. Protonation at this site leads to significant conformational changes necessary for the fusion process, including the destabilization and opening of the S4 helix and the observation of FP release in the protonated systems. These findings illuminate the complex and detailed dynamics of Sav1866 and HA0. The insights gained could inform structure-based drug discovery, offering potential applications in drug design, biotechnology, and precision medicine where understanding protein dynamics is critical for developing effective and selective treatments.

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